Clinical Research Group Chronic Airway Diseases, Medical Faculty, Philipps-University Marburg, Marburg, Germany.
Am J Respir Crit Care Med. 2010 Apr 1;181(7):705-17. doi: 10.1164/rccm.200804-573OC. Epub 2009 Dec 10.
Emphysema is characterized by destruction of alveoli with ensuing airspace enlargement and loss of alveoli. Induction of alveolar regeneration is still a major challenge in emphysema therapy.
To investigate whether therapeutic application of palifermin (DeltaN23-KGF) is able to induce a regenerative response in distal lung parenchyma after induction of pulmonary emphysema.
Mice were therapeutically treated at three occasions by oropharyngeal aspiration of 10 mg DeltaN23-KGF per kg body weight after induction of emphysema by porcine pancreatic elastase.
Airflow limitation associated with emphysema was largely reversed as assessed by noninvasive head-out body plethysmography. Porcine pancreatic elastase-induced airspace enlargement and loss of alveoli were partially reversed as assessed by design-based stereology. DeltaN23-KGF induced proliferation of epithelium, endothelium, and fibroblasts being associated with enhanced differentiation as well as increased expression of vascular endothelial growth factor, vascular endothelial growth factor receptors, transforming growth factor (TGF)-beta1, TGF-beta2, (phospho-) Smad2, plasminogen activator inhibitor-1, and elastin as assessed by quantitative reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry. DeltaN23-KGF induced the expression of TGF-beta1 in and release of active TGF-beta1 from primary mouse alveolar epithelial type 2 (AE2) cells, murine AE2-like cells LA-4, and cocultures of LA-4 and murine lung fibroblasts (MLF), but not in MLF cultured alone. Recombinant TGF-beta1 but not DeltaN23-KGF induced elastin gene expression in MLF. Blockade of TGF-signaling by neutralizing antibody abolished these effects of DeltaN23-KGF in LA-4/MLF cocultures.
Our data demonstrate that therapeutic application of DeltaN23-KGF has the potential to induce alveolar maintenance programs in emphysematous lungs and suggest that the regenerative effect on interstitial tissue is linked to AE2 cell-derived TGF-beta1.
肺气肿的特征是肺泡破坏，随之而来的是肺泡空间扩大和肺泡丧失。诱导肺泡再生仍然是肺气肿治疗的主要挑战。
研究治疗应用 palifermin（DeltaN23-KGF）是否能够在诱导肺气肿后诱导远端肺实质的再生反应。
在诱导肺气肿后，通过口咽抽吸每公斤体重 10mg DeltaN23-KGF 的方式对小鼠进行三次治疗。
通过非侵入性头出体描记术评估，与肺气肿相关的气流受限得到了很大的逆转。通过基于设计的体视学评估，猪胰弹性蛋白酶诱导的肺泡空间扩大和肺泡丧失得到了部分逆转。DeltaN23-KGF 诱导上皮细胞、内皮细胞和成纤维细胞增殖，与增强的分化以及血管内皮生长因子、血管内皮生长因子受体、转化生长因子（TGF）-β1、TGF-β2、（磷酸化）Smad2、纤溶酶原激活物抑制剂-1 和弹性蛋白的表达增加有关，通过定量逆转录-聚合酶链反应、Western 印迹和免疫组织化学评估。DeltaN23-KGF 诱导 TGF-β1 在原代小鼠肺泡上皮 2 型（AE2）细胞、鼠 AE2 样细胞 LA-4 和 LA-4 与鼠肺成纤维细胞（MLF）的共培养物中的表达，并从其中释放活性 TGF-β1，但不在单独培养的 MLF 中表达。重组 TGF-β1 而非 DeltaN23-KGF 诱导 MLF 中的弹性蛋白基因表达。中和抗体阻断 TGF 信号转导可消除 DeltaN23-KGF 在 LA-4/MLF 共培养物中的这些作用。
我们的数据表明，治疗应用 DeltaN23-KGF 有可能在肺气肿肺中诱导肺泡维持程序，并表明对间质组织的再生作用与 AE2 细胞衍生的 TGF-β1 有关。
